Regenerative Medicine Breakthroughs

Will BioTime Reset the Clock of Aging?

By Julius Goepp, MD

iPS: From Vision to Reality

Dr. West’s exciting work at publicly traded BioTime, Inc. is aimed at making that vision a reality on the fast track. West’s team is working on a “reprogramming matrix.” BioTime recently licensed patents Dr. West had filed years before the publication of papers on human iPS cells that cover the use of the iPS genes in turning back the clock of human aging. “The goal is to use this material to permanently re-engineer old cells (say from a 100-year-old person), and bring them back to cells indistinguishable from those they were born with 100 years earlier.

“We’re faced with a ‘tsunami’ of aging,’” West says, “and with the age wave of the baby boom generation, the timing is right for us as a nation to utilize these technologies to offer lower-cost therapies for crippling diseases like arthritis, for example. If we can rebuild the cartilage in your joints so you can walk to the store, the cost savings alone to this country would be just enormous. Many people have no idea that this emerging field of regenerative medicine was born of a desire to find a means to regenerate tissue function in the aged human and directly address this enormous human need.

“Now that we can turn back the arrow of time on human cells, the next question is how to learn how to make the cell types we need in a purified form and industrial scale for a host of age-related diseases. The good news here is that we’ve made some remarkable progress already.”

The challenge Dr. West refers to is that scientists still don’t understand just how stem cells “figure out” what kind of tissue they are destined to turn into. During natural embryonic development, there are specific genetic codes that seem to help cells “recognize” their environment, so that a cell developing at a location past the elbow joint turns into part of a wrist, a hand, or a finger—and never into an upper arm or a shoulder.25-27 “In some primitive animals,” West points out, “an arm amputated above the elbow regenerates with a normal elbow and everything beyond it—but if the amputation is below the elbow, the limb grows back without producing a second elbow.”

So today’s stem cell researchers must “decode” the cells’ intricate and complex position-finding mechanism—a daunting task considering the thousands of cell types and subtypes in the body, which not only have to form properly, but then must work together correctly. Or is that arduous decoding actually necessary? According to West, absolutely not.

Using a bold new approach, West’s lab simply exposes stem cells to a “shotgun” mix of conditions, and then uses modern genetic techniques to figure out what they’ve produced. “Instead of looking up at the apple tree and saying, ‘we want to pick that particular apple right there,’ West says, “we just lay out a tarp on the ground and shake the tree. It’s a random approach, but it is turning out to be very powerful—we produced 140 different cell types in just our first experiment alone.” Each of those 140 types is known as an embryonic progenitor cell—more advanced than a stem cell, but still capable of developing into many cells of a particular tissue type—say cells in the musculoskeletal system, or blood cells, or even nervous system tissue.28 These cells may have the capacity to “recognize” their environment when injected into injured or aged tissue, and proceed to develop into appropriate cell types and even organize themselves into functioning tissue based on the environment in which they find themselves.

“The bottom line,” Dr. West says, “is that for the first time, medicine has an all-powerful stem cell to make everything in the human body, and young cells of any kind can be generated that are genetic matches to the patient who needs them. The hope—I would even say the anticipation—is that we’ll be able to fulfill the vision of regenerative medicine, which is to make cells for an old person just like those they were born from decades earlier. They can be used to regenerate at least some aspects of the human body’s function, whether it be the heart or the hair cell of the inner ear to restore hearing, and so on.”

Embryonic Stem Cells Derived From Human Embryos

2-4: The resulting embryo divides three times over the next three days.

5: By around day five, the blastocyst embryo has developed and consists of an inner cell mass of stem cells and an outer layer that will form the placenta. The stem cells would differentiate into the various tissues of a fetus.

6: Here, the stem cells are removed and cultured.

7: Different tissue types may be grown, including bone marrow and skin.

8: Youthful stem cells are developed into therapies, which are injected into the body to regenerate tissues and treat disease.

Induced Pluripotent Stem Cells Transformed From Adult Skin Cells

Skin cells removed from apatient are transformed by genes in a Petri dish into rejuvenated immortal cells, which are then developed into biocompatible therapies that are administered to the patient to regenerate tissues and treat disease.

The Bright Future of Stem Cell Therapy

In wrapping up, we ask Dr. West to speculate cautiously which of the major age-related diseases might be addressed with the new technology within the lifetime of people reading this article.

“First I think it’s important to understand that we’re very early in the dawn of this phase of medicine. The Bush administration’s highly ill-advised restrictions on funding in this area continue to hamper progress, though California has stepped up to the plate with three billion dollars to advance the field. But with those caveats, I’m still terribly excited about how we can potentially affect some of the largest aspects of aging.”

“There’s an old adage in gerontology,” West continues, “that ‘you’re only as old as your arteries.” In fact, children afflicted with catastrophic premature aging diseases such as progeria and Werner’s syndrome have the identical, short-telomere-induced cardiovascular changes as people literally 10 times their age.29 “We can actually see vascular endothelial cells getting old by measuring their telomeres—the cells “know” in a sense that there’s something terribly wrong, and then send out signals that arrest normal blood flow, accelerate clotting, and produce inflammatory signals that cause immune cells to invade the vessel wall—that’s what produces cardiovascular disease.”

“Well, could we fix that? At my previous company, we showed that it is possible to make young circulating precursors that can become either blood vessel cells or actual blood cells. We could actually label those cells and watch them traffic through the blood and see them land in damaged vessels and patch the damage. So we believe that if you could infuse the aged human with these cells, we could not only give older people a younger immune system, but we could potentially repair their vasculature as well.” In fact, human studies now bear out these cells’ potential for stimulating vessel growth in ischemic tissues.30,31

What About the Risk of Cancer?

You may be wondering whether the telomere “clock” helps cells “know” when to die, and prevents them from out-of-control growth. “There’s no evidence that switching on telomerase, the enzyme that keeps germ cells immortal, interferes with normal developmental pathways or cell control mechanisms,” Dr. West says. “Telomerase doesn’t force a cell to keep reproducing, it just allows it to reproduce if and when it’s called upon to do so.”

“Think about it,” he continues. “When you’re young and have a whole lifetime of telomere length in your cells, they don’t flip right out of control just because they have great proliferative reserves. And so resetting the telomere clock would not be predicted to have impact on normal development—skin cells would still slough off on cue and so on, just as they did when you were young. It’s just that the cells that produce them remain young themselves—they just don’t run out of time.”

So is the implication that one can not only stop further aging with this technology, but perhaps actually reverse some existing changes? “There are animal data to suggest that,” Dr. West responds. In fact, a quick search of the medical literature for 2008 alone reveals the following astonishing discoveries:

iPS cells from patients with the crippling paralytic disease, amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s disease), can be directed to develop into functioning motor nerve cells;32 injection of stem cells into humans has already been shown to be safe and effective at slowing ALS disease progression.33

Laboratory and animal studies have shown that musculoskeletal stem cells can be directed to develop into functional bone and cartilage cells with physical characteristics similar to young healthy bones and joints.34-37

Neural-derived stem cells have improved status of mice with Huntington’s disease, promoted recovery in rats with ischemic stroke, and are being explored as potential therapy for patients with brain tumors.38-40

Summary

“We are always accused of hyping all this,” Dr. West says wryly as we end our conversation. “I believe that with time, people will begin to understand the basis of our excitement. The problem is that so many people still believe that aging is inevitable—what they don’t understand is the immortality of the species. I know this defies common wisdom, but common wisdom is perhaps wrong: the reality is that we’re born from cells that have been proliferating since the dawn of life on Earth. That’s just the way it is.”

“As scientists, we’ve got this duty to find ways to clarify truth and dispel myth. We have to explain that aside from the innumerable circus shows, snake oil salesmen, and all that, there’s really serious gerontology at work. Molecular biology today is able to do experiments a thousand times faster and better than it could even 10 years ago, and it’s leading to some really dramatic breakthroughs. Our tools are just so powerful these days. I conceive of the day when we can engineer embryonic stem cells at a molecular level and create new kinds of cells that never existed even in nature.”

Dr. West readily acknowledges that it’s impossible to tell just how far this technology can take us. But with more than 6,000 studies on stem cells published in 2008 alone, it’s clear we are privileged witnesses to a genuine scientific revolution. Will BioTime succeed in reversing the aging of human cells? Must we continue to succumb to aging-related disease and death? Or can we harness the power of our undying cell lineages to achieve a taste of immortality? Only time will tell.

Glossary of Terms

Embryonic stem cells: Cells derived from embryos developed from eggs fertilized in a laboratory that are capable of differentiating into all cell types in the body.

Germ-line cell: Cells containing genetic material that can be passed on from generation to generation.

Induced pluripotent stem cells (iPS): Cells that can differentiate into numerous cell types; typically derived from differentiated adult somatic cells in the laboratory via exposure to certain genes. Although they are functionally equivalent to embryonic stem cells, they are not derived from an embryo.

Somatic cell: Differentiated cells within the body of an organism, aside from gametes (eggs and sperm). Somatic cells have a finite life span.

Telomere: Repetitive DNA sequences at the ends of chromosomes that protect the chromosomes from destruction. Shortening of telomere length leads to reduction of cell replication.

Telomerase: The enzyme that elongates telomeres, which are typically shortened after each cycle of cell replication.

In the meantime, the Life Extension Foundation continues to contribute funding to Dr. West’s pioneering research.

Dr. West is the Chief Executive Officer of BioTime, Inc. and Embryome Sciences, Inc. of Emeryville, California and Adjunct Professor of Bioengineering at the University of California, Berkeley. You can contact Dr. West at mwest@biotimemail.com.

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